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Current Clinical Trials of Epothilone B Analog (BMS-247550)

Current Clinical Trials of Epothilone B Analog (BMS-247550)

BMS-247550 is a methyl, semi-synthetic analog of the natural
product epothilone B. Provided to the National Cancer Institute (NCI) by
Bristol-Myers Squibb, BMS-247550 was chosen for clinical development because it
demonstrated antitumor activity in paclitaxel (Taxol)-sensitive, paclitaxel-insensitive,
and paclitaxel-resistant human tumor models. The first NCI-sponsored clinical
trial of BMS-247550 was initiated in February 2000.

Taxanes represent one of the most effective classes of anticancer
therapeutics; however, many human cancers either do not respond to or become
resistant to taxane-based therapy. Therefore, screening programs have sought
microtubule-stabilizing compounds with a broader range of activity and/or
activity against taxane-refractory cancers. Fermentation products in the culture
broth of the cellulose-degrading myxobacteria Sorangium cellulosum were found to
have antifungal and cytotoxic activity. German investigators isolated
epothilones A and B from this culture broth and elucidated their
structures.[1,2]

Bollag and colleagues found that the epothilones A and B induce
polymerization of tubulin and enhance microtubule stability.[3] The epothilones
compete with the taxanes for binding to tubulin, suggesting a single
pharmacophore for these two classes of agents. The epothilones’ microtubule
stabilization causes mitotic arrest and therefore, precipitates cell-cycle
arrest at the G2/M transition, with resultant apoptosis.[4] The epothilones,
unlike the taxanes, retain their activity against P-glycoprotein-expressing,
multiple drug-resistant tumors and cell lines as well as tumors resistant to
the taxanes based on tubulin mutations.[3]

Epothilone B, unlike paclitaxel, does not elicit endotoxin-signaling pathways
in murine macrophages, yet the effects of microtubule stabilization are
preserved. Therefore, the production of proinflammatory cytokines and nitric
oxide seen with paclitaxel has not been observed with epothilone B.[5]
These preclinical data raise the possibility that the antitumor effects of
paclitaxel may be preserved in epothilone B, whereas some adverse reactions—such
as arthralgias and myalgias—associated with a proinflammatory state, may not.

Investigators at Bristol-Myers Squibb conducted an extensive screening
program of more than 300 semisynthetic analogs of epothilones A and B.
BMS-247550, a lactam analog of epothilone B, emerged as the leading candidate
for further development, having outperformed paclitaxel in a series of
preclinical tumor models.[6]

Preclinical Studies

BMS-247550 has demonstrated a broad spectrum of activity against a panel of
tumor lines in vitro, including human ovarian, breast, prostate, colon, lung,
and epithelial cancer lines and leukemia cell lines. Median inhibitory
concentration (IC50) values were between 1.4 and 34.5 nM, based on a 72-hour
exposure. BMS-247550 retained its activity against paclitaxel-resistant lines,
compared to paclitaxel-sensitive lines. Tubulin polymerization assays
demonstrated a 2.5-fold greater potency for BMS-247550 over paclitaxel.
BMS-247550 causes virtually complete cell-cycle arrest in G2/M at 7.5 nM, which
is approximately the mean IC90 in vitro.[6]

Mouse tumor models, including models of mouse fibrosarcoma and human
pancreatic, ovarian, colon, and breast cancers have shown that log cell kill of
BMS-247550 is equal or superior to that of paclitaxel in both paclitaxel-sensitive
and -resistant tumors in virtually all cases, when the drugs are administered
according to their respective optimal doses and schedules.

Preclinical data suggest that the efficacy of BMS-247550 may be
schedule-dependent. A study of A2780 (ovarian) tumors in mice demonstrated a
less frequent dosing schedule, allowing for higher doses to be administered,
with a maximum tolerated dose of 16 mg/kg per injection on an every-4-days ×
3
schedule vs 6.3 mg/kg per injection on an every-2-days ×
5 schedule.

Similar results were demonstrated in an HCT116 (colon) model: A maximum
tolerated dose of 24 mg/kg per injection on an every-8-days ×
2 schedule vs 6.3
mg/kg per injection on an every-2-days × 5 schedule. In both of these models,
the antitumor effects were markedly superior in the mice treated on the
intermittent schedules as well.[6] In two other studies in the Pat-7
(pancreas) and HCT116/VM46 (paclitaxel-resistant colon) tumors, the efficacy of
two IV treatment schedules (every 2 days × 5 and every 4 days × 3) were
compared, and in both cases, the two regimens yielded essentially equivalent
antitumor activities.

BMS-247550 is bioavailable orally. Experiments with the HC116 (colon) mouse
tumor model have demonstrated that the antitumor activity of oral BMS-247550 is
identical to that of the intravenous regimen.

Clinical Studies

Phase I studies of BMS-247550 evaluating three schedules are ongoing and have
been reported in abstract form.

Adverse reactions attributed to BMS-247550 have included neutropenia,
arthralgia/myalgia, fatigue, weakness, constipation, diarrhea, nausea, vomiting,
rash, alopecia, and peripheral neuropathy. Dose-limiting toxicities on the
every-21-day schedule are neutropenia, neuropathy, and arthralgia/myalgia, and
the maximum tolerated dose on this schedule is 50 mg/m² per cycle. The maximum
tolerated doses of the every-7-day and 5 × daily every-21-day schedules have
not yet been defined, but the patterns of toxicity are similar thus far, with
the possible exception of diminished neuropathy on the daily × 5 days schedule.
BMS-247550 is administered in Cremaphor EL solution, and hypersensitivity
reactions have been observed in patients who were not premedicated. There have
been no reports of clinically relevant hypersensitivity in patients receiving H1
and H2 blockers as premedication.[7-11]

Preliminary pharmacokinetic and pharmacodynamic studies in humans demonstrate
a wide volume of distribution for BMS-247550 (399-1157 L/m²) and a terminal
half-life of approximately 1 to 2 days, with a clearance of 230 to 423 mL/min/m2.[12]
Enhanced tubulin polymerization in peripheral blood mononuclear cells has been
seen at several dose levels. Plasma area under the concentration-time curve (AUC)
values appear to be proportional to dose.

Preliminary evidence of antitumor activity has been reported on all schedules
under investigation and has included the following tumor types: ovarian, colon,
breast, melanoma, non-small-cell lung, anal, and head and neck
cancers.[7,9-11]

The Cancer Therapy Evaluation Program (CTEP) at the NCI is sponsoring a broad
range of phase I and II clinical trials of BMS-247550, both as a single agent
and in combination with other agents on various schedules. Bristol-Myers Squibb
is sponsoring trials in patients with breast, colorectal, gastric, melanoma, and
non-small-cell lung cancer. The following list includes approved and/or active
clinical trials examining treatments with the epothilone B analog BMS-247550,
which are being sponsored by CTEP. Information about these studies can be
obtained from the principal investigator or the contacts listed for each trial,
or from A. Dimitrios Colevas, MD, at CTEP (colevasd@ctep.nci.nih.gov),
301-435-9128.

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